The state-dependency in obstructive sleep apnea implies that the disorder could be treated with pharmacotherapies countering the sleep-related loss of dilator nerve excitation. Many of the hypoglossal motoneuron excitatory receptor subtypes have been identified. Recently, however, we observed that long-term intermittent hypoxia (LTIH), modeling oxygenation patterns in moderate-severe sleep apnea, results in reduced excitation of hypoglossal nerve activity in response to locally applied serotonin and glutamate agonists. But we must now determine if other upper airway dilator nerves are equally affected by LTIH (Aim 1A) and then begin to elicit the mechanisms underlying LTIH motor nerve impairments. In our preliminary studies, we have found carbonylation of proteins increased in motor nuclei. A carbonylation reaction likely to occur and accumulate in motoneurons and impair function is the formation of oxidized advanced glycation end products (CMLAGE) on neuronal proteins. We will next determine if LTIH-carbonyl AGE accumulation occurs in parallel with impaired excitatory neurochemical responses in multiple upper airway motoneuronal pools (Aim IB). The importance of AGE must be substantiated by preventing AGE accumulation in LTIH and showing improved nerve responsiveness (Aim 1C). Previous work and our preliminary results suggest microglia activation by CMLAGE at the AGE receptor resulting in NAD(P)H oxidase activation; this in turn increases extracellular superoxide that oxidizes AGE in motoneurons and microglia resulting in impaired function and release of more CML-AGE to trigger further NAD(P)H oxidase activation. We will substantiate the importance of NAD(P)H oxidase with a series of complementary pharmacological and transgenic models of reduced NAD(P)H oxidase activity, showing preservation of nerve function following LTIH, and reduced oxidative injury including carbonyl AGE production (Aim2). In vivo studies should be complemented with in vitro studies to determine the microglial role in LTIH nerve injury and AGE production (Aim 3). Another common source of AGE in humans is chronic hyperglycemia, as in diabetes. Diabetes is present in many adults with sleep apnea. We believe diabetes increases AGE production and thus, places persons with sleep apnea at greater risk of LTIH nerve injury. In the final Aim, we will use mouse and rat models of diabetes to determine if chronic hyperglycemia worsens LTIH induced AGE accumulation and LTIH nerve injury, and if careful glucose control may prevent the injuries from LTIH (Aim 4). Collectively, the proposed studies will unveil important mechanisms of neuronal injury in obstructive sleep apnea and should reveal diabetes is a risk factor for this neural injury in sleep apnea.